Pseudomonas aeruginosa, as well as methicillin resistant Staphylococcus aureus MRSA, is one of major causative organisms of nosocomial infections. Since these bacteria have multidrug resistance, the treatment of these bacterial infections is difficult, presenting a serious problem in clinical settings. These bacteria acquire drug resistance by drug efflux pump. This pump uses energy to actively transport and discharge drug that has entered inside of the bacteria. Since the drug efflux pump of Pseudomonas aeruginosa can discharge a variety of antibiotics with different structures, Pseudomonas aeruginosa is resistant to a variety of drugs.
Pseudomonas aeruginosa is gram negative bacteria with two membranes, outer membrane and inner membrane. In order for drug to be discharged, the drug must be actively transported via these two membranes. The drug efflux pumps are classified into several families. Among them, pumps of RND (resistance nodulation division) family consist of three subunits. Pseudomonas aeruginosa has a plurality of RND pumps. Among them, the major pump is MexAB-OprM pump.
As schematically shown in FIG. 1, a MexAB-OprM pump has drug transporter MexB in the inner membrane, and OprM that forms a pore to transmit drug in the outer membrane. These membranes form a complex where MexA connecting the inner and the outer membrane exists in periplasm. Drug in the cell is directly discharged via this complex.
The amino acid sequence of the protein constituting MexAB-OprM pump has already been determined, and its conformation is being investigated using various methods including X-ray analysis (non-patent document 1). Attempts have been made to inhibit the pump function in order to enhance the effect of antibiotics. For example, in patent document 1, pharmacophore that is predicted by the relation between conformation and inhibitory effect of a compound that is expected to inhibit the pump is identified, and synthesis of a compound that satisfies the condition necessary for the pharmacophore is being attempted. However, this method is not practical because it involves screening of an immense number of compounds in order to identify a compound that can inhibit the pump function.    Non-patent document 1: Hiroyuki Akama et al., J. Biological Chemistry, Vol. 279, 52816-52819 (2004).    Patent document 1: Japanese published unexamined application 2002-128768